Research Newsletter-Fall/Winter 2010

NUTRITION AND IMMUNITY, PART 2

Summary: Deficiencies of zinc, selenium, iron, and copper
adversely affect immune response. Conversely, too much
iron and copper impair immune function. Probiotics—microorganisms
often added to dairy products like yogurt—improve immune function in
the gastrointestinal system and
may help prevent inflammatory bowel disease. Obesity
produces chronic inflammation and compromised immunity
that may increase the susceptibility to inflections. Moderate,
regular exercise may enhance immunity, but prolonged
high-intensity exercise may impair it.

Part 1 of this article discussed the differences between the
innate and adaptive immune systems and focused on the
role of macronutrients (protein and lipids) and vitamins.
In part 2, I discuss the role of minerals and other dietary
and lifestyle factors in immunity.

Several nutritionally-essential minerals, including zinc,
selenium, iron, and copper, play important roles in the
development and expression of immune responses.
Zinc is
required for both innate and adaptive immunity because it
has various catalytic, structural, and regulatory functions in
the body. Inadequate intake of zinc can lead to a nutritional
deficiency of the mineral and compromised immune function.
For instance, zinc deficiency impairs the complement system,
a biochemical network of more than 30 proteins in plasma
and on cell surfaces that functions to kill invading pathogens
by direct lysis (cell rupture) or through the promotion of
phagocytosis. Phagocytosis is a process by which certain
immune cells, such as macrophages, engulf and digest
invading microorganisms and foreign particles. Zinc
deficiency also impairs other components of innate immunity,
including natural killer cell activity and the ability of immune
cells to generate oxidants that kill invading pathogens, as
well as production and function of lymphocytes—cells that
are key to mounting an adaptive response. Adaptive immune
responses, which are more complex than innate responses,
provide antigen specificity and immunologic "memory" of
pathogens; the latter makes subsequent responses to the same
pathogen more efficient. For example, vaccines function by
this process so that subsequent exposure to the pathogen
elicits a fast and efficient immune response. Zinc deficiency
results in a heightened vulnerability to several infectious
agents. In particular, children with zinc deficiency have
increased susceptibility of infectious diarrhea, and zinc
supplementation reduces the frequency, severity, and duration
of diarrheal episodes in young children. Zinc supplementation
in children may also reduce the incidence of lower respiratory
infections like pneumonia. However, because of conflicting
studies, it is presently not clear whether zinc supplementation
has utility in treating childhood malaria.

Selenium is
required for normal function of several
enzymes important in innate and adaptive immunity,
including the glutathione peroxidases—key redox regulators
and cellular antioxidants. Inadequate intake of selenium
can impair multiple immune responses, such as cytokine
(cell-signaling molecules) expression, antibody production,
and aspects of cell-mediated immunity. Selenium deficiency
has been shown to enhance the virulence or progression of
some viral infections. For example, mouse studies have
shown that a relatively harmless strain of coxsackievirus
becomes more virulent in selenium-deficient mice, resulting
in an inflammation of the heart muscle called myocarditis.
In humans, concomitant selenium deficiency and
coxsackievirus infection may both contribute to the
cardiomyopathy in Keshan disease. Additionally, small
controlled trials in individuals who were not overtly selenium
deficient have found that short-term supplementation
with selenium enhances immune cell response to foreign
antigens. Other studies have established selenium to be
an important regulator of cytokine expression.

Iron is required
by the host to mount an effective
immune response because the mineral is needed in the
differentiation and proliferation of T lymphocytes and in the
generation of reactive oxygen species that kill pathogens.
Accordingly, iron deficiency—the most prevalent micronutrient
deficiency in the world—results in impaired
immunity and increased morbidity and mortality from
infections. However, iron is required by most infectious
agents for replication and survival, and during the early
stages of an infection, serum levels of iron decrease and
ferritin (a protein that stores iron) levels increase in order
to sequester iron from pathogens. Moreover, elevated iron
levels, such as in untreated hereditary hemochromatosis
(a genetic condition of iron overload despite normal iron
intake), can impair phagocytic function, cytokine production,
complement system activation, as well as the function of B
and T lymphocytes. Further, elevated iron levels may be a
risk factor for cancer and death, especially in men. Since
iron is very efficiently recycled in the body and lost only
in blood and skin sloughing, the Linus Pauling Institute
recommends that men and postmenopausal women who
are not at risk of iron deficiency take a multivitaminmineral
supplement that does not contain iron.

Copper is
also important in immunity, but the exact
mechanism of its immune action is not yet known.
Nutritional deficiency of copper results in an abnormally
low number of neutrophils, a condition called neutropenia.
Menkes disease is a genetic disorder of intracellular copper
transport. Individuals with Menkes disease suffer from
severe copper deficiency and frequent, serious infections.
It is currently unknown if marginal or mild copper
deficiency results in impaired immunity, but high intakes
of copper for prolonged periods have been shown to
adversely affect immune function.

Dietary factors other than nutrients may affect immunity,
as well. For instance, yogurt and other fermented foods
may contain probiotics, which are live microorganisms
that benefit the overall health of the host when they are
administered in sufficient amounts. Bacteria of the
Lactobacilli and Bifidobacteria species are common
examples. These and other probiotics can transiently
inhabit the lower gastrointestinal tract and modulate
immune function by interacting with intestinal epithelial
cells and immune cells. Studies have shown that probiotics
can benefit both innate and adaptive immunity; however,
immune modulation requires regular consumption of
probiotics since they have not been shown to permanently
alter intestinal microflora. Specific immune effects include
strengthening the intestinal epithelial barrier and stimulating
production of antibodies and T lymphocytes—important
mediators of the adaptive immune response. Immune effects
of probiotics may depend on the particular strain, as well as
the dose, route, and frequency of delivery. While probiotics
may have utility in the prevention of various diseases, such
as inflammatory bowel disease, diarrheal diseases, allergic
diseases, and gastrointestinal infections, more clinical
studies are currently needed to elucidate their health effects.

While certain nutritional deficiencies, like some of the
mineral deficiencies mentioned above, can compromise
immunity, oversupply of nutrients may also be associated
with untoward immune effects. Overnutrition is a form of
malnutrition where nutrients, especially macronutrients,
are supplied in excess of the body's needs. Overnutrition
can create an imbalance between energy intake and energy
expenditure, leading to excessive energy storage and obesity.
Obesity is a major public health problem in the United
States and elsewhere because the condition is associated
with increased risk of morbidity from a number of chronic
diseases, including hypertension and other cardiovascular
diseases, type 2 diabetes, liver and gallbladder disease,
osteoarthritis, sleep apnea, and various cancers. Moreover,
obesity is linked to an increased risk of overall mortality.

Obesity has been shown to alter immunocompetence.
In obesity, immune cells called macrophages infiltrate
adipose (fat) tissue and accumulate in numbers proportional
to the degree of obesity. Macrophages and other immune
cells play important roles in the development of inflammation.
Inflammatory processes are triggered in part by molecules
secreted by adipose tissue. A chronic state of low-grade
inflammation exists in obesity. Adipose tissue secretes a
number of fatty acids, cytokines, and hormones that are
involved in inflammatory and immune processes. The
hormone leptin is secreted from adipose tissue and
circulates in direct proportion to the degree of fat stores.
Leptin is an important regulator of food intake, body
weight, and energy homeostasis. Results of animal and in
vitro studies indicate that leptin also modulates inflammatory
and other immune responses, such as stimulation of proinflammatory
cytokine production. Immune modulation
that occurs in obesity could increase the susceptibility of
obese individuals to infections. Some epidemiological studies
have shown that obese patients have a higher incidence of
postoperative and other hospital-related infections compared
with patients of normal weight. Obese individuals have also
been shown to exhibit poor wound healing and increased
occurrence of skin infections.

An increased vulnerability, severity, or complications of
certain infections in obesity may be related to a number of
factors, such as select micronutrient deficiencies. In fact,
deficiencies or inadequacies of the B vitamins and vitamins
A, C, D, and E have been associated with obesity, probably
because energy-dense but micronutrient-poor foods are
consumed. Certain mineral deficiencies may also be linked
to obesity. For example, one study in obese children and
adolescents associated impairments in cell-mediated
immunity with deficiencies in zinc and iron. Overall, immune
responses appear to be compromised in obesity, but more
research is needed to clarify the relationship between
obesity and infection-related morbidity and mortality.

In addition to dietary factors, lifestyle choices may play
a role in immunity. Moderate, regular physical activity
decreases biomarkers of systemic inflammation and may
also enhance immune function, especially in sedentary
individuals. In contrast, high-intensity exercise for prolonged
periods (≥90 minutes) increases levels of C-reactive
protein—a biomarker of cardiovascular and systemic
inflammation—and may temporarily compromise responses
of both innate and adaptive immunity. However, the effects
of exercise on immune responses are probably influenced
by a number of variables, including a person's age, genetics,
overall health and nutritional status, as well as the type,
intensity, and duration of exercise. More clinical research
is needed to determine whether exercise-induced changes
in immune functions translate to altered risk of various
infections, such as the common cold and other respiratory
tract infections.